Construction of a circRNA-miRNA-mRNA Regulatory Network Reveals Potential Mechanism and Treatment Options for Osteosarcoma

Abstract

BackgroundOsteosarcoma is a common malignant primary bone tumor in adolescents and children. Numerous studies have shown that circRNAs were involved in the proliferation and invasion of various tumors. However, the role of circRNAs in osteosarcoma remains unclear. Here, we aimed to explore the regulatory network among circRNA-miRNA-mRNA in osteosarcoma.MethodsThe circRNA (GSE140256), microRNA (GSE28423), and mRNA (GSE99671) expression profiles of osteosarcoma were collected from the Gene Expression Omnibus (GEO) database. Differentially expressed circRNAs, miRNAs and mRNAs were identified. CircRNA-miRNA interactions and miRNA-mRNA interactions were determined by Circular RNA Interactome (CircInteractome) database and microRNA Data Integration Portal (mirDIP) database, respectively. Then, we constructed a regulatory network. Function enrichment analysis of miRNA and mRNA was performed by DIANA-miRPath v3.0 and Metascape database, respectively. mRNAs with significant prognostic value were identified based on expression profiles from The Cancer Genome Atlas (TCGA) database, and we constructed a subnetwork for them. To make the most of the network, we used the CLUE database to predict potential drugs for the treatment of osteosarcoma based on mRNA expression in the network. And we used the STITCH database to analyze and validate the interactions among these drugs and mRNAs, and to further screen for potential drugs.ResultsA total of 9 circRNAs, 19 miRNAs, 67 mRNAs, 54 pairs of circRNA-miRNA interactions and 110 pairs of miRNA-mRNA interactions were identified. A circRNA-miRNA-mRNA network was constructed. Function enrichment analysis indicated that these miRNAs and mRNAs in the network were involved in the process of tumorigenesis and immune response. Among these mRNAs, STC2 and RASGRP2 with significantly prognostic value were identified, and we constructed a subnetwork for them. Based on mRNA expression in the network, three potential drugs, quinacridine, thalidomide and zonisamide, were screened for the treatment of osteosarcoma. Among them, quinacridine and thalidomide have been proved to have anti-tumor effects in previous studies, while zonisamide has not been reported. And a corresponding drug-protein interaction network was constructed.ConclusionOverall, we constructed a circRNA-miRNA-mRNA regulatory network to investigate the possible mechanism in osteosarcoma, and predicted that quinacridine, thalidomide and zonisamide could be potential drugs for the treatment of osteosarcoma.

Comprehensive analysis of hypoxia-related genes for prognosis value, immune status, and therapy in osteosarcoma patients

“…CYFIP2 is well-recognized as a p53-driven proapoptotic protein with low expression levels in gastric cancer (Jackson et al, 2007;Jiao et al, 2017). Similar to the conclusions of He Y et al (He et al, 2021), we believe that RASGRP2 is a risk factor for the prognosis of osteosarcoma patients. RASGRP2 can inhibit apoptosis by activating Rap1 to down-regulate the production of TNF-induced ROS (Takino et al, 2019).…”

Differentially expressed miRNAs in bone after methotrexate treatment

“…Numerous studies have attempted to construct regulatory networks among key miRNAs–mRNAs in diverse pathological models. Recently, a circRNA–miRNA–mRNA regulatory network in osteosarcoma has revealed the potential molecular mechanisms and therapeutic approaches for osteosarcoma (He et al, 2021). X. Liu et al (2020) constructed a comprehensive breast cancer‐related PPI network and miRNA–mRNA interaction map through miRNA array and functional enrichment analyses.…”

“…Numerous studies have attempted to construct regulatory networks among key miRNAs-mRNAs in diverse pathological models. Recently, a circRNA-miRNA-mRNA regulatory network in osteosarcoma has revealed the potential molecular mechanisms and therapeutic approaches for osteosarcoma (He et al, 2021). X.…”

Advances in the Biological Functions and Mechanisms of miRNAs in the Development of Osteosarcoma

“…Studies on the mechanisms of competitive endogenous RNAs(ceRNAs) have been continuously reported in recent years. 172 And more recently, the lncRNA–miRNA–mRNA axis, 173 circRNA–miRNA–mRNA regulatory networks, 174 etc, lay a theoretical foundation for in-depth study of the specific action mechanism of miRNAs, which can also provide better strategies for the diagnosis and treatment of osteosarcoma. Through continuous research on the role and mechanism of miRNAs in the development of osteosarcoma, we will guide the continuous improvement of the theoretical system of miRNAs, so that miRNAs can play a more significant role in clinical benefits.…”